Pancreatic cancer is a complex and lethal disease with a dismal 5-year survival rate (<5%). Because it is usually diagnosed in an advanced stage with no curative therapies, developing novel strategies to prevent or delay the progression of pancreatic cancer is of utmost importance. We propose to study phospho-valproic acid (P-V), a novel derivative of valproic acid (VPA), in combination with cimetidine, a clinically available antiulcer compound, as a novel drug combination for pancreatic cancer prevention. P-V is twice as effective against pancreatic cancer as VPA. For example, in xenograft models P-V reduces tumor growth by 68%, compared to control, whereas VPA reduces it by 34% (chemoprevention protocol). Remarkably, when given in combination with cimetidine, P-V completely prevents the growth of pancreatic tumors in the same animal model. P-V appears to be safe, as shown by genotoxicity and animal toxicity studies, and its key mechanism of action is the inhibition of STAT3 at the mitochondrial level. Our hypothesis is that P-V + cimetidine is an effective and safe chemopreventive drug combination against pancreatic cancer. To test this hypothesis, we will pursue the following specific aims: Aim # 1: Determine the chemopreventive efficacy of P-V + cimetidine in preclinical models of pancreatic cancer; Aim # 2: Determine the mechanism of action of P-V + cimetidine in vitro and in vivo. At the completion of these studies, we expect to have determined key pharmacological parameters of a promising novel drug combination approach for pancreatic cancer prevention. Given the importance of pancreatic cancer and the lack of effective chemopreventive agents against it, we believe that the proposed work holds the promise of a significant advance in this area.